Method for manufacturing lactulose anhydride

ABSTRACT

The present invention provides a method for manufacturing lactulose anhydride, which comprises drying lactulose trihydrate at a temperature within a range of from 45° to 75° C. and a degree of vacuum within a range of from 25 to 100 Torr to remove water of crystallization. 
     The method of the present invention permits manufacture of lactulose anhydride through a simple process, at a high yield and at a low cost, and is therefore suitable for mass production of lactulose anhydride in an industrial scale.

TECHNICAL FIELD

The present invention relates to a method for manufacturing lactuloseanhydride. More particularly, the present invention relates to a methodfor mass production of lactulose anhydride useful as a growth factor ofBifidobacterium, a medical drug for hepatic encephalopathy and the like,simply and at a low cost.

BACKGROUND ART

Upon discovery, lactulose had been prepared from an alcoholic solutionin the form of anhydrous lactulose crystal (hereinafter sometimesreferred to as "anhydride") [Journal of American Chemical Society, Vol.52, p. 2101, 1930]. Since then, lactulose has been believed to beprepared by forming an anhydride. More recently, it was reported thatlactulose trihydrate crystal (hereinafter sometimes referred to as"hydrate") was available from an aqueous solution [CarbohydrateResearch, Vol. 6, p. 29, 1992].

As lactulose is a substance useful as a growth promoting factor ofBifidobacterium and a medical drug for hepatic encephalopathy, variousmanufacturing methods have so far been developed.

When manufacturing lactulose, obtaining a hydrate from an aqueoussolution is preferable to obtaining an anhydride from an alcoholicsolution, from the points of view of simplicity, safety and economicadvantages.

Lactulose is on the other hand commercially produced in the form of asyrup or powder. For the convenience in handling, commercial productionin a powdery form is preferable. Lactulose is not however suitable forproducing into a powdery product because of a high water-solubility, andparticularly such a low melting point as 68.1° C. of the hydrate,resulting in melting at a temperature of about 58° to 60° C.

The anhydride has in contrast such a high melting point as 169° C. andis stable even in a powdered state, leading to an important value ofuse. There is therefore an increasing demand for a manufacturing methodwhich is safe and simple as that of the hydrate.

From such a point of view as described above, the present inventorsinvented a method for converting a hydrate into an anhydride, and filedan application for a patent under the title of a method formanufacturing crystalline lactulose anhydride (Japanese PatentApplication No. 03-272,841; Japanese Patent Provisional Publication No.05-111,400; hereinafter referred to as the "prior application"). Themethod of this prior application comprises the steps of dryingcrystalline lactulose trihydrate dried at the room temperature, underthe atmospheric pressure and at a temperature within a range of from 45°C. to the melting point, and then drying same at a temperature of up to80° C.

The method of the prior application has made it possible to eventuallyobtain lactulose anhydride from an aqueous solution, not from analcoholic solution, as described above.

Even in this excellent method of the prior application, however, therestill remain problems to be solved before application in an industrialscale. More specifically, the method of the prior application hasdrawbacks in that, since crystalline lactulose trihydrate is dried by,for example, the fluidized-bet drying method, crystalline lactulosefines scatter, resulting in a decrease in the final product yield, andthat the fluidized-bet drier is large in size and high in cost.

DISCLOSURE OF INVENTION

The present invention has an object to provide a novel method whichpermits manufacture of lactulose anhydride by a simple process, at ahigh yield and at a low cost by improving the method of the priorapplication described above while retaining the favorable features ofthe latter.

As a mean for achieving the above-mentioned object, the presentinvention provides a method for manufacturing lactulose anhydride, whichcomprises drying lactulose trihydrate at a temperature within a range offrom 45° to 75° C. and at a degree of vacuum within a range of from 25to 100 Torr to remove water of crystallization.

A preferred embodiment of the method of the present invention comprisesstarting drying of lactulose trihydrate at a temperature within a rangeof from 45° to 60° C. and at a degree of vacuum within a range of from30 to 60 Torr while stirring the trihydrate, then gradually heating thetrihydrate, and removing water of crystallization while stirring at atemperature within a range of from 60° to 70° C. and at a degree ofvacuum within a range of from 30 to 60 Torr.

The method of the present invention as described above makes it possibleto convert hydrate into anhydride keeping a powdery state, and tomanufacture lactulose anhydride at a high yield by a simple processcomprising heating and pressure reduction without using a solvent suchas alcohol at all for removing water of crystallization. The method ofthe present invention is suitable for industrial application because ofthe possibility of easily expanding the scale, and is economicallyadvantageous because of the use of a compact and inexpensive facility.

BEST MODE FOR CARRYING OUT THE INVENTION

The same hydrate not as yet dried as in the prior application can beused as the starting material for the method of the present invention,an example of which is as follows.

The lactulose syrup used in the manufacture of the hydrate may be onemanufactured by a known method (for example, Japanese Patent No.874,954), or a commercially available one. In addition to water, thelactulose syrup usually contains 45 to 55% (weight percentage; the sameapplies also hereafter unless otherwise specified) lactulose, 2 to 8%galactose, 2 to 5% lactose, and 2 to 8% other sugars, with a purity oflactulose in solids of from 70 to 90%. This usual lactulose syrup may bedirectly used without purifying. With a lactulose concentration of under70% in solids, substances other than lactulose are more liable tocrystallize, and separation of hydrate becomes difficult.

Since the lactulose syrup contains lactose having a low solubility,lactose crystals should preferably be removed as far as possible inorder to obtain a hydrate. For this purpose, the sugar-in-water ratio oflactose [lactose content/(lactose content+water content)] is kept below10%, and total solids are concentrated to 65 to 75%. With a total solidconcentration of under 65%, lactulose is not supersaturated, resultingin no precipitation of hydrate or in a precipitation at a low yield. Atotal solid concentration of over 75% leads in contrast to a highviscosity of the lactulose syrup which is difficult to handle.

Then, the concentrated lactulose syrup is cooled to a temperature offrom 2° to 20° C. and seed crystals are added (seeding) for lactuloseand stirred to cause precipitation of crystals. The temperature ofcrystal precipitation should preferably be the lowest possible, andlarger crystal should be precipitated through slow cooling. A hydrate isdesirable as lactulose for seeding. Crystals of hydrate are sufficientlycaused to grow, and then the hydrate is separated by a known method (forexample, the centrifugal filtration method or the decantation method).The separated hydrate is washed with water to remove impurities.Considering the high solubility of hydrate, washing should preferably beconducted with the smallest possible amount of cold water. Because theresultant hydrate is in a state wetted with water, it is necessary toremove water from the surface. When the hydrate contains free water, thehydrate is dried at the room temperature under the atmospheric pressureor under vacuum to substantially eliminate free water, and then theresultant dried hydrate is used as the starting material in the presentinvention.

In the method of the present invention, as will be clear from a testexample described later, an anhydride is available by drying the hydrateat a temperature within a range of from 45° to 75° C. and at a degree ofvacuum within a range of from 25 to 100 Torr and eliminating water ofcrystallization. The anhydride is available under any conditions withinthe above-mentioned ranges of conditions, whereas more preferable mannercomprises the steps of, first, starting drying of the hydrate at atemperature within a range of from 45° to 60° C. and at a degree ofvacuum within a range of from 30 to 60 Torr while stirring, thengradually heating the dried hydrate, continuing drying at a temperatureof from 60° to 75° C. and a degree of vacuum of from 30 to 60 Torr whilestirring, and thus almost completely eliminating water ofcrystallization from the hydrate, whereby an anhydride is available. Theheating rate, which may be arbitrarily selected as a rule, should morepreferably be within a range of from 0.2° to 0.6° C./minute.

An anhydride is a substance available by removing water ofcrystallization from a hydrate. There is therefore conceivable a generaldrying method using drying by heating or vacuum drying. It is howeverdifficult to practically carry out these methods. This will be provedbelow by showing Tests in which an anhydride obtained by these generalmethods is compared with an anhydride available by the method of thepresent invention.

Test 1

A hydrate prepared by the same method as in the Example 1 (meltingstarting point: 58° to 60° C.) was dried at a temperature of 60° C.under one of the following values of pressure for six hours. The resultsof measurement of properties of the resultant samples are shown in Table1.

Sample 1-1: Atmospheric pressure, using a drier (purchased from ToyoSeisakusho);

Sample 1-2: Under vacuum of 30 Torr, using a vacuum drier (purchasedfrom Yamato Kagaku Co.);

Sample 1-3: Under vacuum of 4 Torr, using a vacuum drier (purchased fromYamato Kagaku Co.).

As is clear from the results shown in Table 1, in the case of dryingunder the atmospheric pressure which is a general drying method (SampleNo. 1-1), crystals melt in the form of small jelly-like balls adheringonto the wall and dried. After leaving in the open air after drying,these balls melt in a honey-like mass by absorbing moisture in the air,thus making it impossible to obtain a stable anhydride. In the case ofdrying under a high vacuum which is another general drying method (4Torr)(Sample No. 1-3), crystals are dried into powder. After leaving inthe open air after drying, the sample showed a strong hygroscopicity,losing fluidity, and showed a change in the form of partialdeliquescence, thus making it impossible to obtain a stable anhydride.

In contrast, the powder of the method of the present invention obtainedthrough drying under vacuum of 30 Torr (Sample No. 1-2), unlike theother powder samples, showed no change after leaving in the open airafter drying, and exhibited a melting point within a range of from 167°to 169° C.

It is evident from these results that a stable anhydride is unavailablewhen a hydrate is dried by heating under the atmospheric pressure ordried under a high vacuum, and a stable anhydride is available only whenthe hydrate is dried under vacuum of 30 Torr according to the method ofthe present invention.

                  TABLE 1                                                         ______________________________________                                        Sample No.  1-1          1-2      1-3                                         ______________________________________                                        Exterior view after                                                                       Powder melts and                                                                           Powdery  Powdery                                     drying for 6 hr.                                                                          firmly adheres to                                                             the container wall                                                Loss on drying (%)                                                                        9.8%         13.0%    13.2%                                       Exterior view after                                                                       Melting into No       Fluidity lost,                              leaving in open air                                                                       honey-like state                                                                           change   and partial                                 for 18 hr.                        deliquescence                               Melting point (°C.)                                                                             167˜169                                        ______________________________________                                    

With reference to the results of the above-mentioned Test 1, thefollowing test was carried out to more clearly determining appropriatetemperature and degree of vacuum for drying.

Test 2

The Test 2 comprised the steps of putting 10 g accurately weighedhydrate prepared by the same method as in the Example 1 in a glassbeaker, placing the hydrate in a vacuum drier (purchased from YamatoKagaku Co.), drying the hydrate at a temperature within a range of from40° to 80° C. and at a degree of vacuum within a range of from 4 to 560Torr for six hours, measuring the weight loss ratio as an indicator ofthe conversion efficiency from hydrate to anhydride, leaving the driedsample in the open air for 24 hours, measuring hygroscopicity, exteriorview and melting point thereof. The results are shown in Table 2.

At a temperature of 40° C., as is clear from Table 2, the weight lossratio is so small that conversion from hydrate to anhydride does notprogress efficiently. This is not therefore practical at all. Atemperature of 80° C. is not desirable because the resultant powderexhibits a tendency toward becoming brownish in color.

A degree of vacuum of up to 20 Torr is not desirable since hygroscopictendency after drying is remarkable, leading to tendency towarddeliquescence and solidification. Conditions including 75° C. and 160Torr, and 60° C. and 560 Torr are not desirable in that the powderpartially melt, becoming a honey-like dried product, with a small weightloss ratio.

By drying the hydrate at a temperature within a range of from 45° to 75°C. and a degree of vacuum within a range of from 25 to 100 Torr, thereis available a stable powder free from hygroscopicity, with a meltingpoint of from 167° to 169° C., showing the same value as that of theanhydride. The present invention is therefore applicable within thisrange. When drying is conducted under a low vacuum as 100 Torr, however,the poor water removing ability requires, in the case of drying with anincreased amount of hydrate, much more time for drying, or the hightemperature for drying results in an increased content of free water,results in mutual bonding of crystals, and then leads to a tendency ofeasily forming lumps. It is therefore particularly recommendable tocarry out drying under vacuum of from 30 to 60 Torr.

When drying is carried out at a temperature of over 60° C. in theinitial stage of drying, crystals tend to melt and adhere to thecontainer wall. It is therefore particularly recommended to conductdrying at a starting temperature within a range of from 45° to 60° C.,gradually increasing temperature, and finally at a temperature within arange of from 60° to 75° C.

Another preferable practice is to improve heat conduction, sufficientlydrying the hydrate as a whole, and carrying out drying while stirringthe hydrate under the above-mentioned conditions of vacuum andtemperature to inhibit adherence of powder.

                                      TABLE 2                                     __________________________________________________________________________    Drying                                                                        temp.                                                                             Degree of vacuum (Torr)                                                   (°C.)                                                                      4       20      25   30   50   100  160    560                            __________________________________________________________________________    40                                                                              A                      2.1                                                    B                      0                                                      C                      Powdery                                                D                                                                           45                                                                              A                 12.8 12.8      12.5                                         B                 0.2  0         0.1                                          C                 Powdery                                                                            Powdery   Powdery                                      D                 167-169                                                                            167-169   167-169                                    60                                                                              A 13.0    13.5    13.2 13.0 13.0 12.8 13.4   6.8                              B 7.5     5.4     0.2  0    0.1  0    0.2    -4.1                             C Partial Partial Powdery                                                                            Powdery                                                                            Powdery                                                                            Powdery                                                                            Powdery                                                                              Partial                            deliquescence,                                                                        deliquescence,                     honey-like,                        solidification                                                                        solidification                     adhering and                                                                  solidifying                      D                 167-169                                                                            167-169                                                                            167-169                                                                            167-169                                                                            167-169                               70                                                                              A                 13.0 13.0      12.8                                         B                 0.1  0         0                                            C                 Powdery                                                                            Powdery   Powdery                                      D                 167-169                                                                            167-169   167-169                                    75                                                                              A                 13.0 12.9      12.8 10.2                                    B                 0.2  0.1       0.1  -0.2                                    C                 Powdery                                                                            Powdery   Powdery                                                                            Partial                                                                       honey-like,                                                                   adhering and                                                                  solidifying                             D                 167-169                                                                            167-169   167-169                                    80                                                                              A                      12.5                                                   B                      0.5                                                    C                      Slightly                                                                      brownish                                               D                                                                           __________________________________________________________________________     (Note)                                                                        A: Weight loss ratio (%) after drying for six hours.                          B: Hygroscopicity (%) after leaving in the open air for 24 hours.             C: Exterior view after leaving in the open air for 24 hours.                  D: Melting point (°C.) after leaving in the open air for 24 hours.

Now, the present invention is described further in detail by means of afew examples. However the present invention is not limited to thefollowing examples.

EXAMPLE 1

Lactulose syrup (made by Morinaga Milk Industry Co., Ltd; comprising, insolids, 85.6% lactulose, 3.1% lactose, 5.2% galactose, and 6.1% othersugars) was concentrated to a sugar-in-water ratio of 7.9% and a totalsolid content of 71.8%. The resultant concentrated liquid in an amountof 100 kg was cooled to 15° C., and 300 g hydrate was added for seeding.The mixture was slowly cooled to 5° C. spending for seven days whilestirring, to prepare hydrate crystals. After the lapse of ten days,crystals were separated from the solution containing crystals of whichthe solid content of the supernatant liquid decreased to 61.3% by meansof a filter cloth type centrifugal separator (purchased from KokusanEnshinki Co.). The separated crystals were washed with cold water at 5°C., thus obtaining about 22.5 kg hydrate crystals. The resultant hydratecrystals were dried at a temperature of 30° C. for eight hours by meansof a vacuum drier (purchased from Kyowa Shinku Co.), thus obtainingabout 20.8 kg dried crystals.

The thus obtained dried crystals had the following physical and chemicalproperties:

1) Water content:

Water content based on the Karl Fischer's method: 14.0%

Water content lost on diphosphorus pentoxide at the room temperature:0.3%

2) Lactulose quantitative assay value:

Quantitative assay value by liquid chromatography based on the methodset out in the United States Pharmacopeia: Twenty-second RevisionSupplement 1, p. 2138, The United States Pharmacopeia Convention, Inc.:85.9%

Calculated hydrate in the material dried over diphosphorus pentoxide atroom temperature: 99.7%

3) Starting point of melting:

Value measured by the capillary method: 58° to 60° C.

This dried hydrate crystal in an amount of 5.0 kg was placed in a vacuumconcentrator (purchased from Mizuho Kogyo Co.), and dried at atemperature of 60° C. and a degree of vacuum of 30 Torr for eight hourswhile stirring, resulting in about 4.1 kg anhydride.

The resultant anhydride was stable as typically represented by ahygroscopicity of 0% after leaving in the open air for 24 hours, and hadthe following property values:

1) Lactulose content:

Quantitative assay value by the same method as above: 99.1%

2) Water content:

After drying at 105° C. for five hours: 0.8%

3) Melting point:

Measured value by the same method as above: 167° to 169° C.

EXAMPLE 2

The dried hydrate crystals obtained in the Example 1 in an amount of 5.0kg were put in a vacuum concentrator (purchased from Mizuho Kogyo Co.),stirred at a temperature of 50° C. under a vacuum of 50 Torr for onehour, and then continuously dried at a temperature of 70° C. under avacuum of 30 Torr for another four hours while stirring, resulting inabout 4.1 kg anhydride.

The resultant anhydride was stable as represented by a hygroscopicity of0% after leaving in the open air for 24 hours, and had the followingproperty values:

1) Lactulose content:

Quantitative assay value by the same method as above: 99.2%

2) Water content:

Assay value by the same method as above: 0.6%

3) Melting point:

Measured value by the same method as above: 167° to 169° C.

EXAMPLE 3

The dried hydrate crystal grains obtained in the Example 1 in an amountof 500 g were spread over a tray, and dried at a temperature of 55° C.under a vacuum of 100 Torr for 15 hours by means of a vacuumconcentrator (made by Yamato Kagaku Co.), giving about 430 g anhydride.

The thus obtained anhydride was stable as represented by ahygroscopicity of 0% after leaving in the open air for 24 hours, and hadthe following property values:

1) Lactulose content:

Assay value by the same method as above: 99.1%

2) Water content:

Assay value by the same method as above: 0.8%

3) Melting point:

Measured value by the same method as above: 167° to 169° C.

Industrial Applicability

The method of the present invention is suitable for mass production inan industrial scale of lactulose anhydride useful as a growth promotingfactor of Bifidobacterium and a medical drug for hepatic encephalopathy.

We claim:
 1. A method for manufacturing lactulose anhydride, whichcomprises drying lactulose trihydrate at a temperature within a range offrom 45° to 75° C. and a degree of vacuum within a range of from 25 to100 Torr to remove water of crystallization.
 2. A method formanufacturing lactulose anhydride as claimed in claim 1, which comprisesstarting drying the lactulose trihydrate at a temperature within a rangeof from 45° to 60° C. and a degree of vacuum within a range of from 30to 60 Torr while stirring, gradually heating the trihydrate, andremoving water of crystallization while stirring the trihydrate at atemperature within a range of from 60° to 70° C. and a degree of vacuumwithin a range of from 30 to 60 Torr.